title: Persistence of LPS-induced lung inflammation in surfactant protein-C-deficient mice.
abstract: Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc(-/-)) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc(+/+) and Sftpc(-/-) mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc(-/-) mice at 3 and 5 days after the final dose. Compared with Sftpc(+/+)mice, inflammatory injury persisted in the lungs of Sftpc(-/-) mice 30 days after the final LPS challenge. Sftpc(-/-) mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc(-/-) type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc(+/+) cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.
authors.affiliation: 1 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Glasser
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Maxfield
authors.forename: Teah L
authors.initials: TL
authors.lastname: Ruetschilling
authors.forename: Henry T
authors.initials: HT
authors.lastname: Akinbi
authors.forename: John E
authors.initials: JE
authors.lastname: Baatz
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kitzmiller
authors.forename: Kristen
authors.initials: K
authors.lastname: Page
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Erik L
authors.initials: EL
authors.lastname: Bao
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001688:Biological Products / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency* / Q000235:genetics; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D001688:Biological Products; D016207:Cytokines; D004731:Endotoxins; C496506:Foxa3 protein, mouse; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D010455:Peptides; D050783:Proto-Oncogene Proteins c-ets; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; C519908:Spdef protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051543:Hepatocyte Nuclear Factor 3-gamma; C044101:endotoxin, Escherichia coli; C072197:beractant